Mammary stem cells(MaSCs),endowed with self-renewal and multilineage differentiation capabilities,are crucial for mammary gland development,function,and disease initiation.Recent advances in MaSCs biology research enc...Mammary stem cells(MaSCs),endowed with self-renewal and multilineage differentiation capabilities,are crucial for mammary gland development,function,and disease initiation.Recent advances in MaSCs biology research encompass molecular marker identification,regulatory pathway dissection,and microenvironmental crosstalk.This review synthesizes key progress and remaining challenges in MaSC research.Molecular profiling advances have identified key markers recently,such as Procr,DII1,Bcl11b,and PD-L1.Central to their regulatory logic are evolutionarily conserved pathways,including Wnt,Notch,Hedgehog,and Hippo,which exhibit context-dependent thresholds to balance self-renewal and differentiation.Beyond intrinsic signaling,the dynamic interplay between MaSCs and their microenvironment,such as luminalderived Wnt4,macrophage-mediated TNF-α signaling,and adrenergic inputs from sympathetic nerves,spatially orchestrates stem cell behavior.In addition,this review also discusses the roles of breast cancer stem cells(BCSCs) in tumorigenesis and therapeutic resistance,focusing on the molecular mechanisms underlying MaSC transformation into BCSCs.Despite progress,challenges remain:human MaSCs functional assays lack standardization,pathway inhibitors risk off-target effects,and delivery systems lack precision.Emerging tools like spatial multi-omics,organoids,and biomimetic scaffolds address these gaps.By integrating MaSCs and BCSCs biology,this review links mechanisms to breast cancer and outlines strategies to target malignancy to accelerate clinical translation.展开更多
Estrogen receptorα(ERα)is an important driver and therapeutic target in∼70%of breast cancers.How ERαdrives breast carcinogenesis is not fully understood.In this study,we show that ERαis a negative regulator of ty...Estrogen receptorα(ERα)is an important driver and therapeutic target in∼70%of breast cancers.How ERαdrives breast carcinogenesis is not fully understood.In this study,we show that ERαis a negative regulator of type I interferon(IFN)response.Activation of ERαby its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes(ISGs),whereas ERαdeficiency or the stimulation with its antagonist fulvestrant has opposite effects.Mechanistically,ERαinduces the expression of the histone 2A variant H2A.Z to restrict the engagement of the IFN-stimulated gene factor 3(ISGF3)complex to the promoters of ISGs and also interacts with STAT2 to disrupt the assembly of the ISGF3 complex.These two events mutually lead to the inhibition of ISG transcription induced by type I IFNs.In a xenograft mouse model,fulvestrant enhances the ability of IFN-βto suppress ERα^(+)breast tumor growth.Consistently,clinical data analysis reveals that ERα^(+)breast cancer patients with higher levels of ISGs exhibit higher long-term survival rates.Taken together,our findings suggest that ERαinhibits type I IFN response via two distinct mechanisms to promote breast carcinogenesis.展开更多
The mammary gland is a dynamic organ that undergoes significant changes at multiple stages of postnatal development.Although the roles of systemic hormones and microenvironmental cues in mammary homeostasis have been ...The mammary gland is a dynamic organ that undergoes significant changes at multiple stages of postnatal development.Although the roles of systemic hormones and microenvironmental cues in mammary homeostasis have been extensively studied,the influence of neural signals,particularly those from the sympathetic nervous system,remains poorly understood.Here,using a mouse mammary gland model,we delved into the regulatory role of sympathetic nervous signaling in the context of mammary stem cells and mammary development.Our findings revealed that depletion of sympathetic nerve signals results in defective mammary development during puberty,adulthood,and pregnancy,accompanied by a reduction in mammary stem cell numbers.Through in vitro three-dimensional culture and in vivo transplantation analyses,we demonstrated that the absence of sympathetic nerve signals hinders mammary stem cell self-renewal and regeneration,while activation of sympathetic nervous signaling promotes these capacities.Mechanistically,sympathetic nerve signals orchestrate mammary stem cell activity and mammary development through the extracellular signal-regulated kinase signaling pathway.Collectively,our study unveils the crucial roles of sympathetic nerve signals in sustaining mammary development and regulating mammary stem cell activity,offering a novel perspective on the involvement of the nervous system in modulating adult stem cell function and organ development.展开更多
基金supported by the National Natural Science Foundation of China(32270837 and 32470849 to C.C.32400661 to M.Z.)the Key Research Project of Hangzhou Institute for Advanced Study(B04006C023001 to C.C.).
文摘Mammary stem cells(MaSCs),endowed with self-renewal and multilineage differentiation capabilities,are crucial for mammary gland development,function,and disease initiation.Recent advances in MaSCs biology research encompass molecular marker identification,regulatory pathway dissection,and microenvironmental crosstalk.This review synthesizes key progress and remaining challenges in MaSC research.Molecular profiling advances have identified key markers recently,such as Procr,DII1,Bcl11b,and PD-L1.Central to their regulatory logic are evolutionarily conserved pathways,including Wnt,Notch,Hedgehog,and Hippo,which exhibit context-dependent thresholds to balance self-renewal and differentiation.Beyond intrinsic signaling,the dynamic interplay between MaSCs and their microenvironment,such as luminalderived Wnt4,macrophage-mediated TNF-α signaling,and adrenergic inputs from sympathetic nerves,spatially orchestrates stem cell behavior.In addition,this review also discusses the roles of breast cancer stem cells(BCSCs) in tumorigenesis and therapeutic resistance,focusing on the molecular mechanisms underlying MaSC transformation into BCSCs.Despite progress,challenges remain:human MaSCs functional assays lack standardization,pathway inhibitors risk off-target effects,and delivery systems lack precision.Emerging tools like spatial multi-omics,organoids,and biomimetic scaffolds address these gaps.By integrating MaSCs and BCSCs biology,this review links mechanisms to breast cancer and outlines strategies to target malignancy to accelerate clinical translation.
基金This work was supported by grants from the State Key R&D Program of China(2022YFA1304900)the National Natural Science Foundation of China(32188101,31830024,31922021,and 32170713)+1 种基金the Fundamental Research Funds for the Central Universities(2042022dx0003)Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2019-/2M-5-071).
文摘Estrogen receptorα(ERα)is an important driver and therapeutic target in∼70%of breast cancers.How ERαdrives breast carcinogenesis is not fully understood.In this study,we show that ERαis a negative regulator of type I interferon(IFN)response.Activation of ERαby its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes(ISGs),whereas ERαdeficiency or the stimulation with its antagonist fulvestrant has opposite effects.Mechanistically,ERαinduces the expression of the histone 2A variant H2A.Z to restrict the engagement of the IFN-stimulated gene factor 3(ISGF3)complex to the promoters of ISGs and also interacts with STAT2 to disrupt the assembly of the ISGF3 complex.These two events mutually lead to the inhibition of ISG transcription induced by type I IFNs.In a xenograft mouse model,fulvestrant enhances the ability of IFN-βto suppress ERα^(+)breast tumor growth.Consistently,clinical data analysis reveals that ERα^(+)breast cancer patients with higher levels of ISGs exhibit higher long-term survival rates.Taken together,our findings suggest that ERαinhibits type I IFN response via two distinct mechanisms to promote breast carcinogenesis.
基金This work was supported by grants from the Ministry of Science and Technology of China(National Program on Key Basic Research Project:2019YFA0802804 to L.Y.)the National Natural Science Foundation of China(31871492 and 32270837 to C.C.)+1 种基金Hubei Provincial Natural Science Foundation(2023AFB784 to Y.X.)the Fundamental Research Funds for the Central Universities(2042022kf1146 to Y.X.and 2042022dx0003).
文摘The mammary gland is a dynamic organ that undergoes significant changes at multiple stages of postnatal development.Although the roles of systemic hormones and microenvironmental cues in mammary homeostasis have been extensively studied,the influence of neural signals,particularly those from the sympathetic nervous system,remains poorly understood.Here,using a mouse mammary gland model,we delved into the regulatory role of sympathetic nervous signaling in the context of mammary stem cells and mammary development.Our findings revealed that depletion of sympathetic nerve signals results in defective mammary development during puberty,adulthood,and pregnancy,accompanied by a reduction in mammary stem cell numbers.Through in vitro three-dimensional culture and in vivo transplantation analyses,we demonstrated that the absence of sympathetic nerve signals hinders mammary stem cell self-renewal and regeneration,while activation of sympathetic nervous signaling promotes these capacities.Mechanistically,sympathetic nerve signals orchestrate mammary stem cell activity and mammary development through the extracellular signal-regulated kinase signaling pathway.Collectively,our study unveils the crucial roles of sympathetic nerve signals in sustaining mammary development and regulating mammary stem cell activity,offering a novel perspective on the involvement of the nervous system in modulating adult stem cell function and organ development.
